Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Death ligands such as CD95 ligand (CD95L) or tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) induce apoptosis in radiochemotherapy-resistant human malignant glioma cell lines. The death-signaling TRAIL receptors 2 (TRAIL-R2/death receptor (DR) 5) and TRAIL-R1/DR4 were expressed more abundantly than the non-death-inducing (decoy) receptors TRAIL-R3/DcR1 and TRAIL-R4/DcR2 in 12 human glioma cell lines. Four of the 12 cell lines were TRAIL/Apo2L-sensitive in the absence of a protein synthesis inhibitor, cycloheximide (CHX). Three of the 12 cell lines were still TRAIL/Apo2L-resistant in the presence of CHX. TRAIL-R2 expression predicted sensitivity to apoptosis. Coexposure to TRAIL/Apo2L and cytotoxic drugs such as topotecan, lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, CCNU) or temozolomide resulted in synergistic killing. Synergistic killing was more often observed in cell lines retaining wild-type p53 activity (U87MG, LN-229) than in p53 mutant cell lines (LN-18, T98G, U373MG). Drug exposure resulted in enhanced TRAIL-R2 expression, but decreased TRAIL-R4 expression in U87MG cells. Ectopic expression of dominant-negative p53(V135A) abrogated the drug-induced changes in TRAIL-R2 and TRAIL-R4 expression, but had no effect on synergy. Thus, neither wild-type p53 function nor changes in TRAIL receptor expression were required for synergy. In contrast, synergy resulted possibly from drug-induced cytochrome c release from mitochondria, serving as an amplifier of the TRAIL/Apo2L-mediated cascade of caspase activation. These data provide novel insights into the role of the TRAIL/Apo2L system in malignant gliomas and illustrate that TRAIL/Apo2L-based immunochemotherapy may be an effective therapeutic strategy for these lethal neoplasms.
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PMID:CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. 1146 79

Overall survival and progression-free survival after 5 and 10 years of 31 patients with malignant glioma treated by a combination of surgery, postoperative radiotherapy, and chemotherapy with a PCV regimen (procarbazine, CCNU [lomustine] and vincristine) is described. Parameters were evaluated by age at diagnosis, gender, ethnic origin, pre- and postsurgery Karnofsky Performance Status (KPS) score, limit and amount of surgical resection, histopathologic type, number of chemotherapy courses, time between surgery and radiotherapy, response to combined therapy, and dosage and type of radiotherapy. Progression-free survival was 29% at 24 months and 22% at 60 and 120 months. Overall survival was 47%, 36%, and 36% after 24, 60, and 120 months, respectively. Favorable prognostic factors for survival in univariate analysis were pre- and postoperative KPS (> or =70; p = 0.015; p = 0.0025, respectively), age of patients (<40; p = 0.01), number of chemotherapy cycles (> or =6; p = 0.02), and radiation dose (> or =60 Gy; p = 0.0015). The only significant prognostic factors for overall survival in a stepwise multivariate analysis were irradiation dose (p = 0.0001), number of chemotherapy cycles (p = 0.001), and preoperative KPS (p = 0.05); for progression-free survival it was number of chemotherapy cycles (p = 0.004). Survival was not affected by excision size, radiation method, histopathologic type of tumor, gender, ethnic origin, or time lapsed between surgery and irradiation.
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PMID:Long-term follow-up in managing anaplastic astrocytoma by multimodality approach with surgery followed by postoperative radiotherapy and PCV-chemotherapy: phase II trial. 1204 Feb 93

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.
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PMID:Adults with newly diagnosed high-grade gliomas. 1205 96

Gliomas are a heterogeneous group of neoplasms that comprise the majority of tumors originating in the central nervous system (CNS). In adults, the most frequently encountered of these are high-grade or malignant neoplasms of astrocytic and oligodendrocytic lineage, ie, anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), and anaplastic oligodendroglioma (AO), respectively. Tumors of mixed lineage are also seen, the most common of which is designated anaplastic oligoastrocytoma (AOA). Standard treatment for these tumors is typically surgery, followed by radiation then chemotherapy. Surgery is required for a definitive histopathologic diagnosis, which in turn will dictate subsequent therapy options. Moreover, aggressive tumor resection improves survival outcomes, and in many cases, the patient's neurologic function. We generally advocate the safest, maximal resection attainable for patients with these tumors as a way to improve prognosis. In almost all cases, surgery is followed by radiation therapy. Postsurgical irradiation is the most effective treatment currently available for improving survival. There is also mounting evidence to suggest that additional radiation, given in the form of brachytherapy or radiosurgery, at initial diagnosis as a "boost" to standard radiation or at tumor recurrence, may provide added improvement in survival outcome. Radiosurgery and brachytherapy are therapies often used to treat eligible patients at this institution. Adjuvant chemotherapy, conventionally given after radiation, may offer a modest survival benefit in some patients with GBM. Bischloroethylnitrosourea (BCNU) is the typical first-line agent used, but chemotherapy seems to be most beneficial in young patients, with little if any impact on survival for patients over 60 years old. At this institution, we often defer treatment with adjuvant chemotherapy for elderly patients with GBM due to lack of efficacy and the attendant risk with chemotherapy. For anaplastic astrocytomas, oligodendrogliomas, and oligoastrocytomas, a commonly accepted standard is adjuvant chemotherapy following irradiation with the three-drug regimen--procarbazine, CCNU, and vincristine (PCV). This is due to an earlier clinical trial that showed a survival advantage in patients treated with adjuvant PCV compared with patients that received BCNU. However, recent data suggest that treatment with either PCV or BCNU may be appropriate. Both regimens now appear to have equal efficacy for anaplastic gliomas in light of a more recent analysis done with larger numbers of patients. AOs are a unique case with respect to tumor chemosensitivity and patient survival. Molecular studies have identified a subpopulation of patients with AO whose tumors have lost chromosomes 1p and 19q. Patients with this molecular pattern have an exceptional responsiveness to PCV chemotherapy and have prolonged survival. Currently, trials are being conducted to confirm this finding and to determine the best treatment regimen for these patients, with particular regard to the timing of radiation and chemotherapy.
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PMID:Malignant gliomas. 1205 53

At the Hungarian National Institute of Neurosurgery 73 recurrent supratentorial malignant tumours were treated by chemotherapy during the last ten years. Chemotherapy was applied after postoperative radiotherapy but in some cases following reoperation only. All cases were clinically and by CT or MRI verified recurrences. Forty-three patients received BCNU-DBD (dibromodulcitol) treatment (23 anaplastic astrocytoma--AA, and 20 glioblastoma multiforme--GM): day 1. BCNU 150 mg/sq.m. in i.v. infusion, day 2. dibromdulcitol 1000 mg/sq orally was given. This course was repeated every six weeks, altogether 2-8 times. Sixteen patients with AA responded with complete or partial regression but only 6 did with GM. Median survival was 14 and 7 months, the difference proved to be significant, p = 0.0091. PCV combination (procarbazine, CCNU, vincristine) was applied to 16 patients with AA and 14 cases with recurrent oligodendroglioma (O). Treatment started with vincristine 1.5 mg/sq.m. i.v. (2.0 mg maximum), the next day CCNU 100 mg/sq.m. was given, followed by procarbazine 60 mg/sq.m. on days 8-22. and finished by the same dose of vincristine on day 30. The course was repeated after one month, mostly six times. Six patients with AA did not respond; in cases of oligodendroglioma all but one responded with complete or partial improvement. It is remarkable that no significant difference was found between the survivals of BCNU-DBD or PCV treated AA patients. Chemotherapy of supratentorial malignant glioma recurrences with nitroso-ureas and their combination proved to be efficacious. It also seems, that in recurrent cases lower grade gliomas show better response rate than glioblastomas.
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PMID:[Chemotherapy of recurrent supratentorial malignant gliomas (phase II study)]. 1212 42

Sodium phenylbutyrate is a biological-response modifier that acts as a dose-dependent inhibitor of glioma cell proliferation, migration, and invasiveness in vitro, possibly by inhibition of urokinase and c-myc pathways. Despite its biological activity in vitro, there have not been any prior reports of efficacy in the treatment of human malignant gliomas. We report a 44-year-old female with a recurrent, multicentric, malignant glioma who experienced a durable remission lasting more than four years. The patient initially presented with seizures caused by a biopsy-proven anaplastic astrocytoma of the frontal lobe. The patient was treated with radiation therapy and Procarbazine-CCNU-Vincristine (PCV). However, the tumor progressed and extended to the corpus callosum with midline shift, refractory to four cycles of continuous 72-h infusion of BCNU/Cisplatinum. Additional enhancing lesions appeared in the left frontal and left temporal lobes. The patient was started on sodium phenylbutyrate, 18 g daily in three divided oral doses, and reduced to 9 g/day and eventually to 4.5 g/day to eliminate mild, reversible side effects. Four years later, the patient has a KPS functional score of 100%. Phenylbutyrate is a well-tolerated, oral agent that shows potential for the treatment of malignant gliomas. Further studies should be considered to identify a subset of patients that have tumors sensitive to phenylbutyrate, either as a single agent or in combination with radiation therapy or other chemotherapeutic agents.
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PMID:Complete response of a recurrent, multicentric malignant glioma in a patient treated with phenylbutyrate. 1501 93

Carboxypeptidase G2 (CPG2) is a powerful prodrug-converting enzyme. Without a requirement for endogenous enzymes or cofactors, it can directly activate mustard alkylating prodrugs to cytotoxic species, killing both quiescent and dividing cells. This paper provides the first report of its use in the context of a clinically relevant delivery vehicle using adenovirus vectors. To strengthen the efficacy of the prodrug-activating system, the enzyme has been engineered to be secreted or glycosylphosphatidylinositol (GPI) anchored to the extracellular membrane of tumor cells, resulting in an enhanced bystander effect by facilitating diffusion of the active drug through extracellular, rather than intracellular, activation. Using the vectors, we have achieved expression of functional secreted or GPI-anchored CPG2 in a panel of tumor cell lines demonstrating no loss in efficacy as a result of GPI anchor retention. Despite variable transduction efficiencies inherent to these vectors, greater than 50% cell kill was achievable in all of the cell lines tested following only a single exposure to the prodrug ZD2767P. Even in cell lines refractive to infection with the vectors, substantial cell death was recorded, indicative of the enhanced bystander effect generated following extracellular prodrug activation. A direct evaluation of the efficacy of our system has been made against adenoviral delivery of herpes simples virus thymidine kinase plus ganciclovir (GCV), a suicide gene therapy approach already in the clinic. In a short-term human glioma culture (IN1760) resistant to the clinical chemotherapeutic drug CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea), thymidine kinase/GCV effected no cell killing compared to 70% cell killing with our system.
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PMID:Adenovirus vector-mediated delivery of the prodrug-converting enzyme carboxypeptidase G2 in a secreted or GPI-anchored form: High-level expression of this active conditional cytotoxic enzyme at the plasma membrane. 1238 28

Over the last decade, the results of 5 prospective clinical trials of intracranial low-grade glioma (LGG) have been published, 4 in adults with supratentorial LGG and 1 in children with infra- and supratentorial LGG. The data from the more than 1600 patients treated on these studies are summarized herein. European Organization for Research and Treatment of Cancer study 22845 randomized 311 adults to postoperative observation or radiation therapy (RT). There was no difference in the 5-year overall survival (OS) rate between the 2 arms. Irradiated patients had a significantly improved 5-year progression-free survival (PFS) rate. European Organization for Research and Treatment of Cancer study 22844 randomized 379 adults to low-dose (45 Gy) versus high-dose (59.4 Gy) RT. Similarly, an intergroup study conducted by the North Central Cancer Treatment Group, Radiation Therapy Oncology Group, and Eastern Cooperative Group randomized 203 adults to low-dose (50.4 Gy) versus high-dose (64.8 Gy) RT. There was no difference in the 5-year OS or PFS rates between the 2 dose groups in either study. A Southwest Oncology Group study randomized 54 adults with incompletely resected LGG to RT alone or RT plus CCNU (lomustine) chemotherapy. There was no difference in outcome between the 2 treatment arms. Important prognostic factors for OS in these 4 adult trials included extent of surgical resection, histology, tumor size, and age. An intergroup study of the Children's Cancer Group and Pediatric Oncology Group enrolled 660 pediatric patients with management based on the extent of surgical resection: Children who underwent gross total tumor resection were observed postoperatively, whereas those who had subtotal resection or biopsy were either observed or administered RT at the discretion of their physician. Survival was most impacted by several prognostic factors, primarily extent of resection. Besides extent of resection, other prognostic factors that were consistent in predicting survival in these 5 clinical trials included patient age and tumor location, size, and histology. The data from these 5 studies indicate that for intracranial LGG in adults, postoperative RT is associated with improved 5-year PFS but not OS rates compared to postoperative observation. Radiation doses of 45 to 54 Gy result in 5-year OS and PFS rates that are similar to those for higher doses. The strategies of chemotherapy alone and RT plus chemotherapy are under investigation. For pediatric LGG, extent of surgical resection is the most important prognostic factor associated with favorable 5-year OS and PFS. Radiation therapy and chemotherapy are generally used in the settings of incomplete resection and recurrent disease, and these strategies are being investigated in prospective clinical trials. The schemata from recently completed and ongoing studies in both adult and pediatric intracranial LGG are reviewed.
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PMID:Prospective clinical trials of intracranial low-grade glioma in adults and children. 1281 21

Over the last decade, the results of four prospective clinical trials of supratentorial low-grade glioma (LGG) in adults have been published. The data from the nearly 1,000 patients treated on these studies are summarized in this presentation, addressing the following three current controversies in the radiotherapeutic management of these patients: (1) optimum timing of radiation therapy (RT); (2) optimum RT dose; and (3) addition of chemotherapy to RT. The 5-year overall survival (OS) and progression-free survival (PFS) rates in these four studies ranged from 58% to 72% and from 37% to 55%, respectively. Significant prognostic factors included extent of surgical resection, histology, tumor size, and age. The European Organization for Research and Treatment of Cancer (EORTC) study 22845 randomized 311 adults to postoperative observation or RT. There was no difference in the 5-year OS rate between the two arms, but the irradiated patients had a significantly improved 5-year PFS rate. EORTC study 22844 randomized 379 adults to low- versus high-dose RT. Similarly, an intergroup study conducted by the North Central Cancer Treatment Group (NCCTG), Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Group (ECOG) randomized 211 adults to low- versus high-dose RT. There was no difference in the 5-year OS or PFS rates between the two dose groups in either study. A Southwest Oncology Group (SWOG) study randomized 60 adults with incompletely resected LGG to RT alone or RT plus lomustine (CCNU) chemotherapy. There was no difference in outcome between the two treatment arms. Further prospective clinical trials are needed to define the optimal management strategy for adults with supratentorial LGG. The schemata from recently completed and ongoing LGG studies will be presented.
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PMID:Current controversies in the radiotherapeutic management of adult low-grade glioma. 1549 18

In a previous publication, we showed that a clinical trial of DL-alpha-difluoromethyl ornithine (DFMO), in combination with PCV (procarbazine, CCNU, vincristine) increased survival of patients with anaplastic gliomas (WHO III) but not glioblastoma multiforme (WHO IV). We believe that treatment outcome (survival) is inversely related to tumor ornithine decarboxylase (ODC) levels. To prove this, we needed to develop an assay to quantify ODC levels in formalin-fixed tumor tissues, which would enable a retrospective study of tumor biopsy specimens from the landmark clinical trial. We developed an assay using a specific polyclonal antibody coupled to an Alexa fluorescent dye. Transgenic MHC-ODC mice with differing levels of ODC in heart muscle were used to establish the relationship between mean gray-scale intensity and enzymatic ODC activity. We found a direct relationship between mean gray-scale intensity of the ODC antibody coupled to Alexa 647 dye and enzymatic activity. Preliminary analysis of a human glioma tissue array shows that tumor-specific variations in levels of ODC can be semiquantitated. We show that mean gray-scale intensity of astrocytoma:glioblastoma is 1:6 and of anaplastic astrocytoma:glioblastoma is 1:4. We also compared the intensity of antibody to Ki67 coupled with phycoerythrin simultaneously in cells but failed to see a relationship that crossed histologies. We conclude that we can measure levels of ODC in formalin-fixed tumor tissue using an antibody to ODC coupled to Alexa 647 dye, and this will enable us to conduct a future study to correlate survival of patients with gliomas of different histologies treated with DFMO to tumor ODC levels.
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PMID:Tissue-based assay for ornithine decarboxylase to identify patients likely to respond to difluoromethylornithine. 1550 41


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